Variant rs910134246 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001071.4(TYMS):c.10G>C(p.Ala4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000795 in 1,258,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

TYMS
NM_001071.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.16

Variant links:

Genes affected

TYMS (HGNC:12441): (thymidylate synthetase) Thymidylate synthase catalyzes the methylation of deoxyuridylate to deoxythymidylate using, 10-methylenetetrahydrofolate (methylene-THF) as a cofactor. This function maintains the dTMP (thymidine-5-prime monophosphate) pool critical for DNA replication and repair. The enzyme has been of interest as a target for cancer chemotherapeutic agents. It is considered to be the primary site of action for 5-fluorouracil, 5-fluoro-2-prime-deoxyuridine, and some folate analogs. Expression of this gene and that of a naturally occurring antisense transcript, mitochondrial enolase superfamily member 1 (GeneID:55556), vary inversely when cell-growth progresses from late-log to plateau phase. Polymorphisms in this gene may be associated with etiology of neoplasia, including breast cancer, and response to chemotherapy. [provided by RefSeq, Aug 2017]

TYMS links:

TYMSOS (HGNC:29553): (TYMS opposite strand RNA)

TYMSOS links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06710714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 7	ENST00000323274.15	NP_001062.1	P04818-1Q53Y97
TYMS	NM_001354867.2 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 6		NP_001341796.1
TYMS	NM_001354868.2 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 5		NP_001341797.1
TYMSOS	NR_171001.1 link	n.450+90C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 7	1	NM_001071.4	ENSP00000315644.10		P04818-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.95e-7

AC:

AN:

1258588

Hom.:

Cov.:

AF XY:

0.00000162

AC XY:

AN XY:

617608

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.78e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.19

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.58

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.66

N;N;N

REVEL

Benign

0.037

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.092

MutPred

0.16

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);

MVP

0.12

MPC

1.1

ClinPred

0.037

GERP RS

-0.99

Varity_R

0.26

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over